Copper (Cu) is an essential trace element for normal growth and development. The dysregulation of Cu homeostasis causes severe human diseases that include Menkes disease, Wilson?s disease, myeloneuropathy, and cardiomyopathy. Cells have evolved sophisticated homeostatic mechanisms for the regulation of Cu acquisition and distribution, and organs communicate to ensure that Cu is distributed appropriately throughout the body, balancing cellular requirements. All organismal Cu must pass through the intestine prior to distribution to other tissues. Therefore, cross-communication must take place among tissue types to ensure that Cu import and export from the intestine are coordinated with extra-intestinal tissue Cu requirements. Based on his postdoctoral work, the PI has proposed an inter-organ regulatory mechanism for Cu homeostasis, as the cardiac-specific knockout mouse of the high-affinity Cu importer, Ctr1 (Ctr1hrt/hrt) exhibited dramatically elevated levels of the ATP7A Cu efflux pump in the liver and intestine, suggesting the existence of an organismal level Cu sensing signal that communicates a cardiac Cu deficiency to the primary site of Cu storage and uptake organ. However, whether this phenotype is a consequence of a pleiotropic cardiac pathology or an organismal Cu homeostasis mechanism remains elusive. The current proposal seeks to identify the molecular nature of this systemic Cu signaling pathway, thereby making significant progress towards our understanding of the roles of systemic Cu deficiency and dysregulation in human health. Furthermore, we plan to include genetic and molecular approaches to identify the mechanisms of cellular and systemic Cu homeostasis by utilizing the genetically tractable and optically amenable animal model Caenorhabditis elegans (C. elegans), as preliminary studies in this organism have established that Cu- homeostasis in C. elegans is tightly regulated and strongly conserved to mammalian Cu absorption. We outline three specific aims to gain insights into how animals regulate and integrate systemic Cu homeostasis: (1) Identify and characterize the molecular mechanisms of organ-specific Cu homeostasis in response to changes in peripheral Cu demands. (2) Identify the inter-organ plasma factor that signals systemic Cu deficiency. (3) Use C. elegans to identify the animal intestinal component responsible for CUA-1 (ATP7A/B) regulation in response to systemic Cu status.